Anja Kruse

Red Blood Cell Lifespan, Erythropoiesis and Hemoglobin Control

Erythropoietin (EPO) and iron deficiency as causes of anemia in patients with limited renal function or end-stage renal disease are well addressed. The concomitant impairment of red blood cell (RBC) survival has been largely neglected. Properties of the uremic environment like inflammation, increased oxidative stress and uremic toxins seem to be responsible for the premature changes in RBC membrane and cytoskeleton. The exposure of antigenic sites and breakdown of the phosphatidylserine asymmetry promote RBC phagocytosis. While the individual response to treatment with EPO-stimulating agents (ESA) depends on both the RBCs lifespan and the production rate, uniform dosing algorithms do not meet that demand. The clinical use of mathematical models predicting ESA-induced changes in hematocrit might be greatly improved once independent estimates of RBC production rate and/or lifespan become available, thus making the concomitant estimation of both parameters unnecessary. Since heme breakdown by the hemoxygenase pathway results in carbon monoxide (CO) which is exhaled, a simple CO breath test has been used to calculate hemoglobin turnover and therefore RBC survival and lifespan. Future research will have to be done to validate and implement this method in patients with kidney failure. This will result in new insights into RBC kinetics in renal patients. Eventually, these findings are expected to improve our understanding of the hemoglobin variability in response to ESA.

Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients

Hyperkalemia is a common life-threatening problem in hemodialysis patients. Because glycyrrhetinic acid (GA) inhibits the enzyme 11beta-hydroxy-steroid dehydrogenase II and thereby increases cortisol availability to the colonic mineralocorticoid receptor, it has the potential to lower serum potassium concentrations. To test this, 10 patients in a 6 month prospective, double-blind, placebo-controlled crossover study were given cookies or bread rolls supplemented with glycyrrhetinic acid or placebo. Twenty-four-hour blood pressure measurements were performed at baseline and week 6 and 12 of each treatment period. The ratio of plasma cortisol/cortisone was significantly increased in all patients on GA as compared to baseline or placebo, indicating appropriate enzyme inhibition. Nine of the 10 patients had a persistent decrease in predialysis serum potassium concentration. On GA, mean predialysis serum potassium was significantly lower than at baseline or on placebo. On placebo, serum potassium was significantly elevated above the upper limit of normal in 76% compared to 30% of measurements during GA treatment. Furthermore, on this treatment the frequency of severe hyperkalemia significantly decreased from 9% to 0.6%. No differences were found in parameters reflecting sodium retention. Although these studies show that prolonged GA supplementation persistently lowers serum potassium in dialysis patients, a long-term toxicity study will be mandatory before we recommend the routine use of this treatment.

Temporal Evolution of Clinical Parameters before Death in Dialysis Patients: A New Concept

Background: Chronic hemodialysis (HD) patients experience an appallingly high mortality in the range of 20% per year. Little is known on the dynamics of key clinical and laboratory variables in the weeks and months preceding death. In order to gain more insight into events preceding death, we embarked on a novel methodological approach which encompasses data analysis from the date of death backwards in time. Methods: The current study investigates the dynamics of postdialytic weight and serum albumin levels in the 24 months preceding death. We performed a retrospective analysis of 2,462 maintenance HD patients who died between July 1, 2005 and April 30, 2008. Patients’ monthly serum albumin levels were extracted for the 24 months preceding the date of death. Similarly, the median weekly postdialysis weight was extracted for the 104 weeks prior to death. Data were analyzed with linear mixed models. Results: Both albumin levels and postdialytic body weight showed a significant decrease irrespective of gender and race in the 3 final months of life. The most pronounced decreases in postdialytic weight and albumin levels were observed in patients with infection as cause of death, the smallest changes occurred in subjects with cerebrovascular events. Conclusions: In their final 3 months of life, HD patients experience a marked decrease in body weight and serum albumin levels. A better understanding of dynamic patterns of key variables before death may be useful in developing processes which alert medical caregivers to patients at increased risk, in order to institute timely diagnostic and therapeutic interventions.

Effects of Dialysate Glucose Concentration on Heart Rate Variability in Chronic Hemodialysis Patients: Results of a Prospective Randomized Trial

Background: Chronic hemodialysis (HD) patients suffer from an appallingly high cardiovascular mortality. During HD, patients are exposed to dialysate glucose, which may alter blood glucose levels and thus exert effects on the autonomic nervous system. Heart rate variability (HRV) is an established indicator of autonomic nervous system activity and a predictor of cardiovascular outcomes. This study investigated the effects of two commonly used dialysate glucose concentrations [100 mg/dl (HD100), and 200 mg/dl (HD200)] on HRV in chronic HD patients. Methods: In this prospective, randomized, controlled, single-masked, cross-over trial, subjects were randomized to receive HD100 or HD200 for a period of 3 weeks followed by a cross-over to the respective other dialysate (www.clinicaltrials.gov #NCT00618033). Blood glucose and insulin levels were measured before and after HD. Intradialytic Holter electrocardiograms were recorded and HRV time domain, frequency domain and complexity parameters analyzed. Results: Twenty-three HD patients (age 56 ± 12 years, 11 male, 14 black, 11 with diabetes) were studied. Diabetic subjects showed significantly higher serum glucose levels with HD200 as compared to HD100 (HD100: 146 ± 48 mg/dl; HD200: 192 ± 57 mg/dl; p < 0.01); this hyperglycemia was accompanied by an increase of the high-frequency band of HRV (p = 0.019), a reflection of increased parasympathetic activity. HRV did not change in nondiabetic subjects. Conclusion: In diabetic subjects, the use of HD200 increased vagal tone. Given the importance of sympathetic activation to counteract intradialytic hypotension, our findings support the use of HD100 in diabetic HD patients.

Metabolic effects of dialyzate glucose in chronic hemodialysis: results from a prospective, randomized crossover trial

BACKGROUND There is no agreement concerning dialyzate glucose concentration in hemodialysis (HD) and 100 and 200 mg/dL (G100 and G200) are frequently used. G200 may result in diffusive glucose flux into the patient, with consequent hyperglycemia and hyperinsulinism, and electrolyte alterations, in particular potassium (K) and phosphorus (P). This trial compared metabolic effects of G100 versus G200. METHODS Chronic HD patients participated in this randomized, single masked, controlled crossover trial (www.clinicaltrials.gov: #NCT00618033) consisting of two consecutive 3-week segments with G100 and G200, respectively. Intradialytic serum glucose (SG) and insulin concentrations (SI) were measured at 0, 30, 60, 120, 180, 240 min and immediately post-HD; P and K were measured at 0, 120, 180 min and post-HD. Hypoglycemia was defined as an SG<70 mg/dL. Mean SG and SI were computed as area under the curve divided by treatment time. RESULTS Fourteen diabetic and 15 non-diabetic subjects were studied. SG was significantly higher with G200 as compared to G100, both in diabetic {G200: 192.8±48.1 mg/dL; G100: 154.0±27.3 mg/dL; difference 38.8 [95% confidence interval (CI): 21.2-56.4] mg/dL; P<0.001} and non-diabetic subjects [G200: 127.0±11.2 mg/dL; G100 106.5±10.8 mg/dL; difference 20.6 (95% CI: 15.3-25.9) mg/dL; P<0.001]. SI was significantly higher with G200 in non-diabetic subjects. Frequency of hypoglycemia, P and K serum levels, interdialytic weight gain and adverse intradialytic events did not differ significantly between G100 and G200. CONCLUSION G200 may exert unfavorable metabolic effects in chronic HD patients, in particular hyperglycemia and hyperinsulinism, the latter in non-diabetic subjects.

A Mathematical Model of Regional Citrate Anticoagulation in Hemodialysis

Background/Aims: Regional citrate anticoagulation (RCA) during hemodialysis (HD) has several advantages over heparin anticoagulation, but calcium (Ca) derangements are a major concern necessitating repeated monitoring of systemic ionized Ca (Ca2+). We developed a mathematical model of Ca and citrate (Ci) kinetics during RCA. Methods: Using patient- and treatment-related parameters, including pre-HD serum Ca and protein concentrations, hematocrit, blood and dialysate flow rates, dialysate composition and access recirculation, the model computes all relevant aspects of RCA based on physicochemical, biochemical and physiological principles such as chemical Ca and Ci equilibria, transmembrane solute fluxes and Ci metabolic rate. The model was validated in 17 treatments using arterial Ci infusion, Citrasate® dialysate, and no postdialyzer Ca substitution. Results: Measured and predicted systemic Ca2+ before HD was 1.08 ± 0.06 and 1.05 ± 0.05 mmol/l, respectively (difference –0.03 ± 0.046, 95% confidence interval, CI, –0.055 to –0.007), and at 15 min into the treatment 1.01 ± 0.05 and 1.02 ± 0.05 mmol/l, respectively (difference 0.012 ± 0.054, 95% CI –0.015 to 0.04). At 15 min, the measured and predicted predialyzer Ca2+ was 0.33 ± 0.06 and 0.39 ± 0.05 mmol/l, respectively (difference 0.06 ± 0.03; 95% CI 0.044–0.077), and the measured and predicted postdialyzer Ca2+ was 0.7 ± 0.05 and 0.61 ± 0.05 mmol/l, respectively (difference –0.09 ± 0.04; 95% CI –0.11 to –0.07). Bland-Altman analysis showed no systematic bias in these predictions. Conclusion: This novel model of RCA shows excellent accuracy in predicting systemic, pre- and postdialyzer Ca2+ concentrations and may prove valuable in both research and clinical applications of RCA.

Clearance of p-cresol sulfate and β-2-microglobulin from dialysate by commercially available sorbent technology.

Dialysate regeneration by sorbents is an alternative to conventional single-pass dialysis. Little is known about the capacity of sorbents to clear dialysate of “middle molecules” and protein-bound uremic toxins. We studied p-cresol sulfate (PCS) and &bgr;-2-microglobulin (&bgr;2M) removal from dialysate by a sorbent:PCS (40 mg PCS dissolved in 4 L of fresh dialysate) was recirculated through a sorbent cartridge (SORB Technology, Inc.) for analysis of PCS removal.Spent peritoneal dialysate was recirculated on the “blood” side of a high-flux dialyzer. On the “dialysate” side of the membrane, bicarbonate dialysate was recirculated through a sorbent cartridge. &bgr;2M was measured in both streams.Two results are of particular importance for the use of regenerated fluid in chronic dialysis:PCS was virtually completely removed from the dialysate. On average, PCS concentration was reduced to 1.4% of the starting concentration after 60 minutes. PCS extraction across the sorbent was nearly complete at any time.&bgr;2M was on average reduced to 14.3% of the starting concentration after 60 minutes. Postsorbent concentrations were consistently below the validated range of the test method.We conclude that PCS and &bgr;2M are efficiently removed from the dialysate by commercially available sorbent technology. Spent peritoneal dialysis fluid can be cleared of &bgr;2M when circulated against sorbent-regenerated dialysate using a high-flux membrane.

Fatigue in Hemodialysis Patients With and Without Diabetes: Results From a Randomized Controlled Trial of Two Glucose-Containing Dialysates

In hemodialysis (HD), dialysate glucose concentrations differ worldwide between 0 and 200 mg/dl and can, if above the serum glucose levels, lead to diffusive glucose shifts into the patient (1). The effects of glucose (2) and insulin (3) on the autonomic nervous system, as well as during HD with different glucose concentrations, (4) have been reported. However the effect of dialysate glucose on fatigue has not been studied. This study investigated fatigue in chronic HD subjects treated with 100 mg/dl (G100) versus 200 mg/dl dialysate glucose (G200). In this randomized, crossover, multicenter study (www.clinicaltrials.gov, NCT00618033), diabetic and nondiabetic patients were enrolled in a 1:1 fashion. Diabetes was defined as either requiring oral antidiabetic medication or insulin or having random blood glucose levels above 200 mg/dl during the preceding 12 months. The study protocol …

Clinical Evaluation of a Model for Prediction of End-Dialysis Systemic Ionized Calcium Concentration in Citrate Hemodialysis

Background/Aim: Citrate anticoagulation in hemodialysis (HD) is increasingly drawing attention in the nephrology community. One of the major deterrents to a more widespread use are the monitoring requirements for fear of systemic calcium derangements. Means of accurately predicting systemic ionized calcium (iCa) may help to overcome this challenge. We have previously presented a mathematical model of regional citrate anticoagulation (RCA) to address this need. Here, we present a refined model and show results in an independent validation cohort of maintenance HD patients on Citrasate®, a calcium- and citrate-containing dialysate. Methods: A hybrid RCA model was developed, comprising the previously published ‘native’ RCA model and a statistical correction based on levels of alkaline phosphatase as a marker of bone turnover. The model was validated in 120 patients on Citrasate, a dialysate containing 0.8 mmol/l citrate and 1.125 mmol/l calcium. Systemic iCa was measured at the beginning and end of one HD treatment in each subject. Serum iCa predictions were compared between our previously published model and the new hybrid model. Results: On average, the hybrid model predicted end-HD systemic iCa with an error (predicted – measured) of 0.028 mmol/l, compared to –0.051 mmol/l with the previously published model. There were only 4 subjects out of the 120 analyzed in whom the prediction error was <–0.1 mmol/l, and only 6 in whom the error was >+0.1 mmol/l (max: +0.13 mmol/l). Conclusion: This study demonstrates that the novel hybrid model is an improvement over the previously published model and that it is capable of predicting end-dialysis systemic iCa levels with improved accuracy and precision even in a citrate dialysis setting which was much different from the original derivation cohort.

Red blood cell life span and ‘erythropoietin resistance’

To the Editor: We read with interest Bamgbolas review on erythropoietin (EPO) resistance in a recent issue of the Journal.1 Although the author presents a wide range of mechanisms and conditions associated with EPO resistance (including ‘accelerated turnover rate of red cells’), the integral role of red blood cell (RBC) life span deserved more explicit elaboration, in our opinion. The response to EPO, meaning the hemoglobin (Hgb) concentration achieved with a certain EPO regimen, is really a continuum rather than a binary outcome, and RBC life span (RBCLS) is a basic component of the process.2, 3 Reduction in RBCLS will necessarily entail a reduction in Hgb unless compensated for by increased RBC production rate (in dialysis patients primarily mediated by EPO and iron therapy). When RBC production cannot increase materially, regardless of increases in EPO dose, a short RBCLS becomes the limiting factor in Hgb increase, giving the impression of resistance to EPO.